Hepatic Manifestations of 3-Hydroxy-3-Methylglutaryl-Coenzyme-A Lyase Deficiency in Saudi Patients: Experience of a Tertiary Care Center

Abstract

3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency, a rare autosomal recessive disorder, is caused by a homozygous or compound heterozygous mutation in the HMGCL gene (chromosome 1p36.11). HMGCL catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Several studies have reported general hepatic findings (e.g., hepatomegaly) in patients with HMGCL deficiency, but currently, there are no available data regarding the incidence and epidemiology of liver involvement. The main objective of our study was to investigate the overall clinical manifestations, laboratory findings, genotype, and presence of hepatic involvement in Saudi patients with HMGCL deficiency. A retrospective chart review of patients with HMGCL deficiency including those with a documented hepatic manifestation was performed at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia. We evaluated 50 cases of HMGCL deficiency. Hepatic findings were found in 17 patients at the time of diagnosis. The mean age of hepatic presentation was 135 days, and the median age was 56 days (range: 2–315 days). Hepatomegaly was found in 65%, abnormal biochemical profile in 47%, and an abnormal imaging in 53% of patients. The most frequent mutation in this cohort was the p.Arg41Gln founder mutation (59%). In comparison to data from the current literature, HMGCL deficiency can be considered as a diagnostic metabolite for hepatic manifestations and requires appropriate evaluation, including molecular genetic analysis.

Keywords

HMGCL deficiency - hepatic manifestations - hepatomegaly - mutation - Saudi Arabia

Publication History

Received: 19 April 2020

Accepted: 11 June 2020

Article published online:
29 July 2020

• References

• 1 Mitchell GF, Fukao T. Inborn errors of ketone body metabolism. In: Scriver CR, Beaudet AL, Sly WS. et al, eds. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill; 2001
• 2 Sass JO. Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis 2012; 35 (01) 23-28
• 3 Matern D. Acylcarnitines, including in vitro loading tests. In: Blau N, Duran M, Gibson KM. eds. Laboratory Guide to the Methods in Biochemical Genetics. Berlin: Springer; 2008: 171-206
• 4 Jörn Oliver Sass JG. Disorders of ketone body metabolism. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C. eds. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Berlin, Heidelberg: Springer-Verlag; 2014
• 5 Grünert SC, Schlatter SM, Schmitt RN. et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients. Mol Genet Metab 2017; 121 (03) 206-215
• 6 Yilmaz O, Kitchen S, Pinto A. et al. [3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review]. Nutr Hosp 2018; 35 (01) 237-244
• 7 Cardoso ML, Rodrigues MR, Leão E. et al. The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. Mol Genet Metab 2004; 82 (04) 334-338
• 8 Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 1988; 148 (03) 180-186
• 9 Ozand PT, al Aqeel A, Gascon G, Brismar J, Thomas E, Gleispach H. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J Inherit Metab Dis 1991; 14 (02) 174-188
• 10 Pié J, López-Viñas E, Puisac B. et al. Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab 2007; 92 (03) 198-209
• 11 Menao S, López-Viñas E, Mir C. et al. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria. Hum Mutat 2009; 30 (03) E520-E529
• 12 Vargas CR, Sitta A, Schmitt G. et al. Incidence of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL) deficiency in Brazil, South America. J Inherit Metab Dis 2008; 31 (Suppl. 03) 511-515
• 13 Gibson KM, Breuer J, Kaiser K. et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: report of five new patients. J Inherit Metab Dis 1988; 11 (01) 76-87
• 14 Urgançi N, Arapoğlu M, Evrüke M, Aydin A. A rare cause of hepatomegaly: 3-hydroxy-3-methylglutaryl coenzyme-a lyase deficiency. J Pediatr Gastroenterol Nutr 2001; 33 (03) 339-341
• 15 Robinson BH, Oei J, Sherwood WG, Slyper AH, Heininger J, Mamer OA. Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome. Neurology 1980; 30 (7 Pt 1): 714-718
• 16 Eirís J, Ribes A, Fernández-Prieto R, Rodríguez-García J, Rodríguez-Segade S, Castro-Gago M. [3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome]. Rev Neurol 1998; 26 (154) 911-914
• 17 Leonard JV, Seakins JW, Griffin NK. beta-Hydroxy-beta-methyglutaricaciduria presenting as Reye's syndrome. Lancet 1979; 1 (8117): 680
• 18 Karcher C, Rousselot JM, Lefebvre E, Vidailhet M. [Hydroxy-methyl-glutaryl-coenzyme A lyase deficiency manifesting as Reye's syndrome in a 3-year-old girl]. Pediatrie 1993; 48 (05) 385-387
• 19 Lee C, Tsai FJ, Wu JY. et al. 3-hydroxy-3-methylglutaric aciduria presenting with Reye like syndrome: report of one case. Acta Paediatr Taiwan 1999; 40 (06) 445-447
• 20 Plöchl E, Bachmann C, Colombo JP, Gibson KM. [3-hydroxy-3-methylglutaraturia. Clinical aspects, follow-up and therapy in a young child]. Klin Padiatr 1990; 202 (02) 76-80
• 21 Muñoz-Bonet JI, Ortega-Sánchez MD, León Guijarro JL. Management and long-term evolution of a patient with 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Ital J Pediatr 2017; 43 (01) 12
• 22 Dasouki M, Buchanan D, Mercer N, Gibson KM, Thoene J. 3-Hydroxy-3-methylglutaric aciduria: response to carnitine therapy and fat and leucine restriction. J Inherit Metab Dis 1987; 10 (02) 142-146
• 23 Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF. Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet 2006; 7: 86
• 24 Mitchell GA, Ozand PT, Robert MF. et al. HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet 1998; 62 (02) 295-300
• 25 Mitchell GA, Robert MF, Hruz PW. et al. 3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency. J Biol Chem 1993; 268 (06) 4376-4381
• 26 Wilson WG, Cass MB, Søvik O, Gibson KM, Sweetman L. A child with acute pancreatitis and recurrent hypoglycemia due to 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Eur J Pediatr 1984; 142 (04) 289-291
• 27 Al Bu Ali WH, Balaha MH, Al Moghannum MS, Hashim I. Risk factors and birth prevalence of birth defects and inborn errors of metabolism in Al Ahsa, Saudi Arabia. Pan Afr Med J 2011; 8: 14
• 28 Gibson KM, Lee CF, Kamali V. et al. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency as detected by radiochemical assay in cell extracts by thin-layer chromatography, and identification of three new cases. Clin Chem 1990; 36 (02) 297-303